A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome.

BACKGROUND: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. METHODS: We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. RESULTS: Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1-7) and angiotensin-(1-5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. CONCLUSIONS: GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.

A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock.

INTRODUCTION: Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. METHODS: In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo. RESULTS: Seventy patients received AZD9773 (n=47) or placebo (n=23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment. CONCLUSIONS: The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies.

Recurrent carbon monoxide poisoning from cigarette smoking.

Carbon monoxide intoxication remains a major cause of morbidity and mortality in the United States with an estimate of 50,000 cases annually in emergency departments nationwide (Weaver, N Engl J Med. 2009;360:1217-25). Sources of carbon monoxide most often include car exhaust, malfunctioning heating systems and inhaled smoke. It has been well established that there is a dose-dependent increase in carboxyhemoglobin (COHb) concentration with tobacco use. It is generally accepted that heavy smokers have COHb levels <10% to 15% (Ernst and Zibrak, N Engl J Med. 1998;339:1603-8). The authors report a 48-year-old woman with significant tobacco abuse who presented with COHb levels as high as 24.2% in the face of tobacco use.

Localization and treatment of bronchopleural fistula through capnography.

Bronchopleural fistula (BPF) is a feared complication in the setting of pneumonectomy, lobectomy, and pulmonary infection. The development of BPFs significantly increases morbidity and mortality, and their treatment is complicated, multifaceted, and variable in success. Recently, the use of fibrin glues, acrylic glues, and endobronchial valves through bronchoscopy has allowed for minimally invasive treatment, sparing the patient surgical intervention. Results in the literature for these modalities have been mostly positive in a variety of clinical scenarios. Regardless of the therapeutic interventions used, proper diagnosis and localization of these fistulas is essential. These modalities have traditionally included installation of methylene blue in the pleural space, balloon occlusion, and ventilation scintigraphy. Here, we report the successful localization and treatment of a BPF through the use of localized bronchoscopic capnography in a 30-year-old woman with a complicated BPF. Initial attempts to localize the fistula with Fogarty catheter balloon occlusion were unsuccessful, as multiple segments were involved. Ultimately, with a capnographic catheter, the precise segments could be identified and subsequently occluded with acrylic glue. Air leak and pneumothorax resolved, chest tubes were removed without complication, and the patient was discharged 2 days after the procedure.

Spontaneous reexpansion of lung tissue after chronic atelectasis due to a stenotic airway.

Chronic atelectasis is a commonly reported complication of bronchial stenosis and airway obstruction. Bronchial stenosis after aspiration of oral medications has been reported in the literature many times. Spontaneous reexpansion of lung tissue after chronic atelectasis due to a stenotic airway is an unusual and unreported phenomenon. We present the case of a 72-year-old woman with documented history of chronic left lower lobe atelectasis due to bronchial stenosis from aspiration of an iron tablet 2 years before the current presentation. Two days after the initial aspiration event, a bronchoscopy was performed with the retrieval of an iron tablet from her left mainstem bronchus (LMB) using saline lavage and suctioning. This appeared successful at the time of the procedure. Repeat imaging of the chest and 2 diagnostic bronchoscopies over the following 2 years revealed near-complete atelectasis of the left lung with occlusion of the LMB. In September 2008, she presented with worsening shortness of breath. On examination, she had absent breath sounds at the left lung base. A chest computed tomography scan revealed scarring of the LMB and left lower lobe atelectasis with improved aeration notable in parts of the lung previously documented to have collapsed. A bronchoscopy revealed an approximately 90% stenosis of the left mainstem LMB. Balloon dilation was performed; although there was significant bronchoscopic improvement noted, the patient did not report any relief of her symptoms from the procedure.

Colonoscopy-associated pneumothorax: a case of tension pneumothorax and review of the literature.

A 64-year-old woman presented with severe abdominal pain and was found to have a large fecolith in the sigmoid colon with resulting bowel obstruction. During a therapeutic colonoscopy, she developed severe shortness of breath and hypoxia, and was found to have a tension pneumothorax. We review the potential mechanisms by which pneumothorax may occur following colonoscopy. In addition, the eight previously published cases are reviewed. Pneumothorax, with or without pneumomediastinum, can occur through a variety of mechanisms following colonoscopy. Although rarely reported, this may represent an underappreciated complication and should be fully investigated in the appropriate setting. Colonoscopy, an exceedingly common procedure, will continue to increase with the aging population. As a result, tension pneumothorax can have a profound effect on the patient outcome and therefore physicians, both gastroenterologists and pulmonologists, should be aware of all the potential problems with this procedure.

Safety in training and learning in the intensive care unit.

Resident and subspecialty fellow trainees in the intensive care unit (ICU) present risks for patient safety because of their inexperience yet offer opportunities to promote safe patient care because of their around-the-clock presence and their involvement in frontline processes of care. Most trainees approach their ICU experiences without previous education in performance improvement or patient safety. This article reviews the barriers that are faced by residents in providing safe patient care and outlines the nature of a patient safety curriculum that could tap the opportunities that are presented by trainees to promote safer patient care.